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Negative Regulation of TLR Responses by the Neuropeptide CGRP Is Mediated by the Transcriptional Repressor ICER¹

Marit D. Harzenetter^*, Alexander R. Novotny^*, Petra Gais^*, Carlos A. Molina, Felicitas Altmayr^* and Bernhard Holzmann^2,*

^* Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; and Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, NJ 07103

Communication between the nervous and immune systems involves the release of neuropeptides, such as calcitonin gene-related peptide (CGRP), from sensory nerves during inflammation. CGRP may inhibit the activities of both innate and adaptive immune cells, but the molecular pathways underlying this function are largely unknown. In this study, we identify CGRP as a potent inhibitor of TLR-stimulated production of inflammatory mediators, such as TNF- and CCL4, by murine dendritic cells. Inhibition of TLR responses was independent of IL-10 and did not involve perturbation of canonical TLR signaling, including activation of MAPK and NF-B. Instead, the inhibitory activity of CGRP was mediated by the cAMP/protein kinase A pathway leading to rapid up-regulation of the transcriptional repressor, inducible cAMP early repressor (ICER). Ectopically expressed ICER directly repressed the LPS-stimulated activity of a synthetic Tnf promoter, as well as TNF- protein production driven by the endogenous promoter. Inhibition of dendritic cell gene expression by CGRP was associated with the presence of a composite cAMP response element/B promoter element. In a murine model of endotoxemia, CGRP markedly attenuated serum TNF- levels, and this effect was associated with the up-regulation of ICER. Together, these results establish a novel pathway for the negative regulation of TLR responses through the nervous system that critically involves induction of the transcriptional repressor ICER by the neuropeptide CGRP.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 576, Project A7) and by the Kommission für Klinische Forschung, Klinikum rechts der Isar.

² Address correspondence and reprint requests to Dr. Bernhard Holzmann, Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany. E-mail address: holzmann{at}chir.med.tu-muenchen.de

³ Abbreviations used in this paper: CGRP, calcitonin gene-related peptide; CRLR, calcitonin receptor-like receptor; RAMP, receptor activity-modifying protein; CGRP-RCP, CGRP receptor component protein; DC, dendritic cell; PKA, protein kinase A; ICER, inducible cAMP early repressor; BMDC, bone marrow-derived DC; 6-Bnz-cAMP, N⁶-benzoyladenosine-3',5'-cAMP; 8-pCPT-2'-O-Me-cAMP, 8-(-4-chlorophenyl-thio)-2'-O-methyladenosine-3',5'-cAMP; Epac, exchange proteins directly activated by cAMP; CRE, cAMP response element; Pam₃Cys, (S)-[2,3-bis (palmitoyloxy)-(2RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys₄-OH.